Immunity and atherosclerosis
Oxidation-specific epitopes in atherosclerosis
During the development of atherosclerotic lesions, low-density lipoproteins (LDL) deposit in the wall of large and medium-sized arteries, where they become oxidized and are taken up by infiltrating macrophages resulting in the formation of foam cells. This process is also characterized by inflammatory reactions and the accumulation of oxidized LDL as well as apoptotic cells in the vascular wall. Notably, both oxidized LDL and apoptotic cells carry the same oxidation-specific epitopes (OSE), which represent danger-associated molecular patterns that are recognized by the innate immune system.
We hypothesize that OSE are key drivers of the inflammatory response in atherosclerosis. Therefore we are investigating how macrophages sense OSE and study the functional consequences of this in the development of atherosclerotic lesions. Key areas include the identification of the receptors and molecular pathways that are mediating these effects, and the development of strategies to inhibit these specific inflammatory responses.
Natural antibodies and the complement system in atherosclerosis
Natural antibodies are pre-existing germline-encoded antibodies that are primarily of the IgM class and secreted by a specialized subset of B1 cells. They play an important role in the first line defense against microbial infections and provide important “house keeping” functions by recognizing damaged self antigens. Natural IgM protect mice from atherosclerotic lesion formation, and data from our group demonstrated that a large part of natural IgM antibodies has specificity for OSE. Ongoing projects focus on the identification of the mechanism by which natural IgM mediate atheroprotection and whether the recognition of OSE is a critical part of this. Moreover, we are pursuing strategies that focus on the therapeutic induction of natural IgM.
More recently we discovered that complement factor H (CFH) specifically binds and neutralizes one type of OSE, namely malondialdehyde modifications. CFH is a major inhibitor of complement activation and genetic variants of it have been associated with a number of disease conditions. We are currently investigating if and how this newly found property of CFH plays a role in atherosclerosis and other inflammatory diseases.
Christoph Binder was born in 1973 in Vienna, Austria. Following his studies of medicine at the Medical Faculty of the University of Vienna, where he obtained his MD degree in 1997, he entered a PhD program at the University of California in San Diego, where he obtained his PhD degree in 2002. In 2005, he joined the Department of Laboratory Medicine at the Medical University of Vienna, where in 2009 he was appointed Professor of Atherosclerosis Research. In 2006, he joined CeMM as Principal Investigator. He is a specialist in laboratory medicine and leads a research group focusing on the role of immune functions in atherosclerosis and how these can be exploited for therapeutic interventions. He first described the atheroprotective effect of pneumococcal vaccination and the natural IgM T15/E06 (Binder et al., 2003). His research group discovered that certain oxidation-specific epitopes derived from lipid peroxidation are major targets of natural antibodies (Chou et al., 2009) and of complement factor H (Weismann et al., 2011). He also identified the protective roles and mechanisms of the cytokines IL-5 (Binder et al., 2004) and IL-13 (Cardilo-Reis et al., 2012), as well as natural IgM antibodies (Gruber et al., 2016; Tsiantoulas et al., 2017; Obermayer et al., 2020) in atherothrombosis. His recent work has also focused on the identification and characterization of mitochondrial extracellular vesicles (Puhm et al., 2019). He has won numerous prestigious fellowships and awards and has authored > 130 publications in renowned journals, including NatureMedicine and Nature.
Puhm F*, Afonyushkin T*, Resch U, Obermayer G, Rohde M, Penz T, Schuster M, Wagner G, Rendeiro AF, Melki I, Kaun C, Wojta J, Bock C, Jilma B, Mackman N, Boilard E, Binder CJ. Mitochondria Are a Subset of Extracellular Vesicles Released by Activated Monocytes and Induce Type I IFN and TNF Responses in Endothelial Cells. Circ Res. 2019 Jun 21;125(1):43-52. (abstract)
Tsiantoulas D, Sage AP, Göderle L, Ozsvar-Kozma M, Murphy D, Porsch F, Pasterkamp G, Menche J, Schneider P, Mallat Z, Binder CJ. B Cell-Activating Factor Neutralization Aggravates Atherosclerosis. Circulation. 2018 Nov 13;138(20):2263-2273. (abstract)
Binder CJ, Papac-Milicevic N, Witztum JL. Innate sensing of oxidation-specific epitopes in health and disease. Nat Rev Immunol. 2016 Aug;16(8):485-97. (abstract)
Gruber S, Hendrikx T, Tsiantoulas D, Ozsvar-Kozma M, Göderle L, Mallat Z, Witztum JL, Shiri-Sverdlov R, Nitschke L, Binder CJ. Sialic Acid-Binding Immunoglobulin-like Lectin G Promotes Atherosclerosis and Liver Inflammation by Suppressing the Protective Functions of B-1 Cells. Cell Rep. 2016 Mar 15;14(10):2348-61. (abstract)
Cardilo-Reis L, Gruber S, Schreier SM, Drechsler M, Papac-Milicevic N, Weber C, Wagner O, Stangl H, Soehnlein O, Binder CJ. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol Med. 2012 Oct;4(10):1072-86. (abstract)
Weismann D, Hartvigsen K, Lauer N, Bennett KL, Scholl HP, Charbel Issa P, Cano M, Brandstätter H, Tsimikas S, Skerka C, Superti-Furga G, Handa JT, Zipfel PF, Witztum JL, Binder CJ. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature. 2011 Oct 5;478(7367):76-81. (abstract)
Chou MY, Fogelstrand L, Hartvigsen K, Hansen LF, Woelkers D, Shaw PX, Choi J, Perkmann T, Bäckhed F, Miller YI, Hörkkö S, Corr M, Witztum JL, Binder CJ. Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J Clin Invest. 2009 May;119(5):1335-49. (abstract)
Binder CJ, Hörkkö S, Dewan A, Chang MK, Kieu EP, Goodyear CS, Shaw PX, Palinski W, Witztum JL, Silverman GJ. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med. 2003 Jun;9(6):736-43. (abstract)
Binder CJ, Chang MK, Shaw PX, Miller YI, Hartvigsen K, Dewan A, Witztum JL. Innate and acquired immunity in atherogenesis. Nat Med. 2002 Nov;8(11):1218-26. (abstract)